Elucidating the role of the SAGA complex in MYCN-amplified neuroblastoma

项目概要/摘要 神经母细胞瘤是婴儿期最常见的肿瘤，导致儿童死亡的人数不成比例 因为癌症相对于成人癌症，儿童癌症具有相对较少的致癌突变，并且大多数儿童癌症具有相对较少的致癌突变。 已知的疾病遗传驱动因素涉及转录因子，而这些转录因子不易被药物控制。的确， 转录因子MYCN的扩增发生在20-25%的神经母细胞瘤中， 风险疾病。由于这种缺乏治疗方法，开发这种疾病的新疗法一直是一个挑战。 “可用药的”基因改变然而，表观遗传失调现在被认为是一个主要的驱动力， 儿科癌症和靶向维持致瘤细胞状态的表观遗传因子提供了一种新的 治疗这些难治性癌症的方法。基因组规模的CRISPR-Cas9功能基因组筛选具有 发现MYCN扩增的神经母细胞瘤细胞依赖于组蛋白修饰的几个成员， Spt-Ada-Gcn 5-乙酰转移酶（佐贺）复合物。重要的是，这种复合物从未在 MYCN扩增的神经母细胞瘤的背景。该提案将解决这一复杂的假设是一个 MYCN扩增的神经母细胞瘤表观遗传状态的关键调节因子，是细胞存活所必需的， 肿瘤维持目的1将发现这种复合物及其组蛋白的遗传和药理学损失 乙酰基转移酶活性影响MYCN扩增的神经母细胞瘤的体外和体内存活。目标2将 阐明佐贺复合物活性对神经母细胞瘤表观遗传景观的贡献， 这种活动的转录后果。这项工作将扩大对表观遗传因素的理解 控制MYCN扩增的神经母细胞瘤，以及建立这种复合物作为一种新的治疗靶点， 这种疾病的临床需求很高。

Project Summary/Abstract Neuroblastoma is the most common tumor of infancy and causes a disproportionate number of children's deaths due to cancer. Pediatric cancers have relatively few oncogenic mutations relative to adult cancers, and most of the known genetic drivers of disease involve transcription factors, which cannot be readily drugged. Indeed, amplification of the transcription factor MYCN occurs in 20-25% of neuroblastomas and is associated with high- risk disease. The development of new therapies for this disease has been a challenge due to this lack of “druggable” genetic alterations. However, epigenetic dysregulation is now appreciated to be a major driver of pediatric cancers and targeting the epigenetic agents that maintain the tumorigenic cell state offers a new approach to treating these intractable cancers. Genome-scale CRISPR-Cas9 functional genomic screens have identified that MYCN-amplified neuroblastoma cells are dependent on several members of the histone-modifying Spt-Ada-Gcn5-acetyltransferase (SAGA) complex. Importantly, this complex has never been studied in the context of MYCN-amplified neuroblastoma. This proposal will address the hypothesis that this complex is a critical regulator of the epigenetic state of MYCN-amplified neuroblastoma and is required for cell survival and tumor maintenance. Aim 1 will discover how genetic and pharmacologic loss of this complex and its histone acetyltransferase activity impacts MYCN-amplified neuroblastoma survival in vitro and in vivo. Aim 2 will elucidate the contribution of SAGA complex activity to the epigenetic landscape of neuroblastoma, and the transcriptional consequences of this activity. This work will expand the understanding of epigenetic factors controlling MYCN-amplified neuroblastoma, as well as establish this complex as a novel therapeutic target in this disease of high-clinical need.